Exposure to DNA damaging insults, such as high level of ROS, UV or ionizing radiation, triggers a well-characterized p53 mediated DNA damage response. This response leads to cell cycle arrest and DNA repair or apoptosis, depending on cell type, proliferative status and the extent of DNA damage. DNA damage can result in genome alterations even when DNA repair response is engaged. This may have long-term consequences for the tissue and organism that experienced DNA damage certain cell types, particularly in stem cells. We have previously found that hematopoietic stem cells can keep track of the past DNA damage for extended periods of time (months to a year) and the relative extent of this past DNA damage determines their competitive status, such that cells with relatively lower levels of past DNA damage outcompete cells that had experienced higher level of damage. Thus our results suggest that cells can remember the DNA damaging insults that happen in the past, even after the DNA repair response has been completed. The purpose of this proposal is to characterize the molecular mechanisms of the memory of DNA damage. Our preliminary studies and proposed experiments should reveal a novel mechanism that controls long-term consequences of tissue exposure to DNA damaging insults. The proposed studies also have obvious implications for the understanding of early stages of tumorigenesis. PUBLIC HEALTH RELEVANCE: Exposure to different types of stress induces an adaptive stress response program that enables the cells to survive the insult. Some forms of stress, notably oxidative stress, UV and ionizing radiation, cause DNA damage, which in turn triggers DNA repair response. We found that cells can keep track of the past insults resulting in DNA damage and the relative extent of the past DNA damage determines the cells competitive status within a population. The goal of this project is to characterize the molecular basis of the memory of DNA damage. The proposed studies should reveal an important biological mechanism that determines the long-term consequences of tissue exposure to DNA damaging insults.